Sleep disturbances occur frequently in neurodegenerative disease and constitute the most common reason for institutionalization. The causes for disturbed sleep are poorly understood and there is no basis for selecting therapeutics based on known mechanistic targets. Sleep disruption has a causal role in increasing amyloid beta (A?) deposition, via orexin signaling, which has fueled interest in targeting orexin signaling in prevention of Alzheimer's Disease (AD). Sleep dysfunction in AD features nocturnal sleep fragmentation, sundowning, and daytime sleepiness as measured by short sleep latencies on the multiple sleep latency test (MSLT). This contrasts with Progressive Supranuclear Palsy (PSP), a tauopathy not associated with A? deposition, which we have shown to feature a marked reduction in duration of both Rapid Eye Movement (REM) sleep and Non- REM (NREM) sleep, and prolonged sleep latencies on the MSLT. The divergent profile of sleep-wake behavior in PSP (dramatic decrease in total sleep time, absent sleep in day) versus AD (redistribution of sleep across night and day periods with minimal reduction is total sleep time)- both neurodegenerative tauopathies beginning in the brainstem and hypothalamus, but only one involving A? deposition - provides an opportunity to refine the understanding on the neurobiological basis of disturbed sleep-wake rhythms enabling the development of disease specific therapeutics. We will test the hypothesis that differential vulnerability of nuclei in wake-promoting (greater loss in AD v PSP) and sleep-promoting (greater loss in PSP v AD) neurons determine the different pattern of sleep wake disturbances in these two tauopathies. The premise of this proposal is that: 1) sleep-wake disturbances are common features of both tauopathies; 2) PSP and AD have distinct localizing foci of neurodegeneration which can be leveraged as naturalistic lesions to uncover neuropathological mechanisms producing different profiles of disturbed sleep and wakefulness; and 3) the future design of efficient and specific treatments for sleep in PSP and AD requires an understanding of the underlying mechanisms. We propose to test if differences in sleep-wake behavior in PSP and AD versus healthy controls (HC) are accounted by differences in quantitative pathoanatomical measures (including numbers of total and specific neuronal population, and hp-tau burden) in nuclei involved in wake and NREM sleep regulation. We will test quantitative clinical histopathological correlates in a subsample who complete sleep measures and undergo autopsy. This project will provide a disease-specific mechanistic rationale for targeting pro-sleep circuits for therapeutics (e.g. GABAergic drugs) versus a wake inhibition approach (e.g. orexin antagonist) in these two disorders.